tbuckley/cabot-search huggingface dataset:
Association of nuclear shape in the tumor epithelium with response to atezolizumab in NSCLC.
Authors: Patrick Leo, Namrata Srivastava Patil, Daniel Ruderman, Jennifer M. Giltnane, Eloisa Fuentes, Amber Schedlbauer, Barzin Nabet, Cleopatra Kozlowski
Journal: Journal of Clinical Oncology (2023)

8543 Background: Anti-PD-(L)1 treatment is the standard of care for advanced non-small cell lung cancer (NSCLC). However, additional biomarkers are needed to identify patients who will benefit from these therapies. In this study, we demonstrate the atezolizumab response score (ARS), which uses digital pathology features of the shape and size of nuclei in the tumor epithelium to predict response to the anti-PD-L1 antibody atezolizumab in NSCLC. Methods: Patients were drawn from two trials comparing atezolizumab to docetaxel in second-line advanced NSCLC. A single digitized slide stained for the epithelial cell marker pan-cytokeratin (CK) and CD8 was selected for each patient. OAK, a phase III trial, had 819 patients with images available and was used for training the ARS model. POPLAR, the phase II trial preceding OAK, had 168 evaluable patient images for validating ARS. Color deconvolution was used to identify the CK-positive regions in each image. Nuclei were segmented using the hematoxylin channel. The area, perimeter, eccentricity, solidity, and minor/major axis lengths were extracted from each nucleus in the CK-positive compartment of the pathologist-annotated tumor lesion, excluding necrosis and artifacts. Each measure’s mean, median, standard deviation, skewness, and kurtosis across the slide was calculated, for a total of 30 features. Features with an interaction p&lt; 0.35 with trial arm in a Cox model were used to fit an elastic-net regularized Cox model on the atezolizumab-treated training set patients, producing ARS. The ARS threshold maximizing atezolizumab overall survival (OS) benefit in the ARS-high group was identified in OAK and applied to POPLAR (the validation set). ARS performance was assessed in the validation set by OS concordance index (c-index) and by atezolizumab benefit in the high- vs. low-ARS groups by hazard ratio (HR) [95% confidence interval]. Results: ARS employs five features. Lower nuclear median and standard deviation of major axis length, higher perimeter mean and standard deviation, and higher area were associated with better atezolizumab response. In the validation set, high-ARS (prevalence = 42%) patients had longer OS on atezolizumab vs. docetaxel (HR = 0.42 [0.24-0.72]) while low-ARS patients did not (HR = 0.95 [0.62-1.47]). ARS was positively associated with OS in the validation set atezolizumab arm (c-index = 0.60 [0.54-0.66]), but not the docetaxel arm (c-index = 0.47 [0.41-0.54]). Conclusions: We validated a nuclear morphology-based biomarker for atezolizumab response in advanced NSCLC. This demonstrates the utility of digital pathology for biomarker development and motivates study into the identified responder phenotype. Combination of ARS with additional markers, such as PD-L1 expression, might further improve stratification.
Comparison of response from RECIST1.1 and abstraction in real-world patients with lung cancer.
Authors: Lu Chen, Ryan Davis, Joe Lee, Janick Weberpals, Shelby Wyatt, Souhila Ounadjela, Huong Trinh, Charlotta Fruechtenicht, Adriana Reyes, Melanie Huntley
Journal: Journal of Clinical Oncology (2023)

e21194 Background: Treatment response in clinical trials with solid tumors is measured by applying RECIST1.1 to radiographic images. However, response in real-world data (RWD) studies is based on information abstracted from clinician's notes. Differences in these two approaches can lead to bias when comparing response in trials to RWD. This study investigates the relationship between response from (1) certified radiologists applying RECIST1.1 to images from routine care and (2) electronic health records (EHR) notes-abstraction in the same patients. Methods: The nationwide Flatiron Health (FH) EHR-derived de-identified database was used to identify patients diagnosed with advanced non-small-cell lung cancer (aNSCLC) on/after Jan 1, 2011, with a visit in the FH network within 90 days of diagnosis, first line treatment (1L), and ≥1 radiographic image both at baseline (8 weeks before or at 1L start) and during 1L. RECIST1.1 and response abstraction were applied retrospectively to images and EHR notes obtained from routine care, respectively. For each patient, time-point responses were determined by RECIST1.1 (rwRECIST) and abstraction (rwR) and dichotomized as unconfirmed best overall response (BOR, complete+partial response = responder, all others = non-responder), and confirmed BOR if patients had an additional assessment. Results: We included 157 patients (59% on chemotherapy, 15%/12% on cancer immunotherapy combination/alone, 10% on targeted therapies). Patients had an image taken every 11 weeks (median). All images were readable and 75% were optimal quality. Response rate was lower by rwRECIST than rwR (unconfirmed: 48% vs 59%; confirmed: 34% vs 55%). Concordance in BOR between rwRECIST and rwR was 68%/60% for unconfirmed/confirmed response. Disagreement between rwRECIST and rwR was higher than inter-reader variability between radiologists and was mainly in one direction (rwR higher, Table). The disagreement was driven by patients deemed responders by abstraction who did not meet the -30% target lesion size cutoff specified by RECIST1.1 or presence of new lesions. Conclusions: RECIST1.1 can be applied to images from aNSCLC routine oncology care, although limited by image availability and less frequent assessment than trials. Differences were observed in response measured by rwRECIST and by abstraction. [Table: see text]
The effect of exercise on physical function and medication adherence in women receiving endocrine therapy for breast cancer: The breast cancer endocrine therapy fitness (BE-FIT) randomized controlled trial.
Authors: Samantha Myers, Nathalie LeVasseur, Kelly Mackenzie, Rafael A. Fujita, Guy Faulkner, Jonathan Berkowitz, Robert Anton Olson, Linda Trinh, Kristin L. Campbell
Journal: Journal of Clinical Oncology (2023)

12069 Background: Approximately 20% of women receiving endocrine therapy (ET) for early-stage breast cancer (BrCa) discontinue their regimen due to side effects, including vasomotor symptoms and arthralgias, subjecting them to higher rates of disease recurrence. Exercise is one approach to mitigate ET-related toxicity and potentially improve medication adherence by mitigating ET-related symptoms. However, only 11% of women with BrCa adhere to recommended exercise guidelines. Purpose: To examine the effect of a virtual supervised exercise program for women receiving ET for early-stage BrCa on physical function (PF) (primary outcome) and adherence to ET (secondary outcome). Methods: Participants were recruited through referral by oncology care providers from multiple BC Cancer sites and self-referral. Eligible participants were: females with stage I-III BrCa being treated with curative intent, 19-75 years, taking ET for at least 3 months up to 3 years. Using a partial cross-over design (NCT04824339), participants were randomized to the immediate exercise group (INT) or the delayed exercise group (CON), which crossed over at 8 weeks. The 8-week intervention was comprised of a 50-minute resistance exercise circuit, delivered virtually by an exercise physiologist twice per week via Zoom, and self-directed aerobic exercise (progressing to 90 minutes or more per week of at least moderate intensity). PF was assessed using the 30-second chair stand test. ET adherence was measured by the Voils self-reported medication non-adherence questionnaire. Values reported as means and standard deviations. The difference at 8 weeks by intervention arm was examined using two sample t-test (continuous) or kappa measure of agreement (categorical). Results: A total of 132 women were randomized. On average, women were 54 years, White (European) (47%), married (64%), had at least a bachelor’s degree or higher (51%), and had a body mass index of 27.7 kg/m 2 . The most common type of ET women received was Letrozole (43%), followed by Tamoxifen (36%). At 8 weeks, there was a significant improvement in PF for INT versus CON (mean change +2.5±2.9 vs. +0.7±2.2 stands, p&lt; 0.001). There was no difference between groups in change in medication adherence status (k = 0.35). Conclusions: An 8-week virtual supervised exercise program for women receiving ET for early-stage BrCa significantly improved PF but did not change medication adherence at 8 weeks. The potential impact of the intervention on long-term medication adherence will be explored up to one year and with covariates. Based on improvement in PF, future trials to establish effectiveness and inform implementation are warranted. Clinical trial information: NCT04824339 .
Cardiac safety of reduced surveillance for cancer therapy related cardiac dysfunction in patients with breast cancer treated with HER2-targeted therapy.
Authors: Anthony Francis Yu, Chau T. Dang, Justine Jorgensen, Chaya S. Moskowitz, Joseph Wallins, Patricia Anne DeFusco, Eric Oligino, Kevin C. Oeffinger, Jennifer Liu, Richard Steingart
Journal: Journal of Clinical Oncology (2023)

12083 Background: Non-anthracycline-based therapy is a treatment option for patients (pts) with HER2-positive breast cancer (BC) and is associated with lower risk of cancer therapy related cardiac dysfunction (CTRCD) compared to anthracycline-based treatment. Given the reduced CTRCD risk with non-anthracycline HER2-targeted therapies, updates to practice guidelines that recommend surveillance echocardiograms (TTE) every 3 months are needed. We evaluated the cardiac safety of reduced CTRCD surveillance in pts receiving non-anthracycline HER2-targeted therapies. Methods: Pts with BC treated with non-anthracycline HER2-targeted therapy were enrolled in this single-arm prospective study. Pts with previous anthracycline exposure, uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg), or significant cardiovascular disease were excluded. TTEs were performed at baseline, 6 months, and 12 months during HER2-targeted treatment. The primary endpoint was a cardiac event, defined by clinical heart failure (New York Heart Association Class III/IV) or cardiovascular death, with a prespecified non-inferiority margin of 2.9% relative to a cardiac event rate of 1.1% based upon prior studies. Secondary endpoints were CTRCD, defined by decline of left ventricular ejection fraction (LVEF) ≥10% to &lt; 53%, and interruption of HER2-targeted treatment secondary to CTRCD. Results: Between May 2019 and January 2022, 190 pts (age 52 ± 11 y) with HER2-positive BC were enrolled: 143 (75%) had stage I disease, 8 (4%) had diabetes, 38 (20%) had hypertension, and baseline LVEF was 64 ± 5% (Table). Additional TTEs outside the prespecified 6- and 12-month timepoints were performed for 35 (18%) pts, of which 20 were to assess for possible cardiac symptoms. After 1-year follow-up, there were 0 (0%; 97.5% CI 0- 1.9%) cardiac events. Two (1.1%) pts developed CTRCD and 1 (0.5%) pt had a temporary CTRCD-related treatment interruption. Conclusions: Reduced CTRCD surveillance every 6 months is feasible and safe for selected pts with HER2-positive BC receiving non-anthracycline HER2-targeted therapy. Our findings support the need to update cardio-oncology practice guidelines and allow for less frequent surveillance TTEs among pts at low-risk for CTRCD. Clinical trial information: NCT03983382 . [Table: see text]
To test, or not to test, that is the question: A real-world analysis of PD-L1 expression testing patterns in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
Authors: Chris M. Black, Gleicy Hair, Dandan Zheng, Lei Ai, Liya Wang, Glenn J. Hanna
Journal: Journal of Clinical Oncology (2023)

6033 Background: PD-L1 expression testing plays an important role in identifying patients who benefit from immunotherapy when treating R/M HNSCC. We aimed to understand how PD-L1 expression testing evaluated by Combined Positive Score (CPS) is used in clinical practice and how testing results impact treatment decision-making. Methods: A retrospective cohort study was conducted using the Flatiron Health Advanced Head and Neck database. We included adult R/M HNSCC patients who initiated first-line (1L) treatment between 07/01/19 and 12/31/21 with follow-up until 06/30/22. Patients were excluded if they received platinum therapy within 6 months prior to 1L treatment, had other primary cancers before advanced diagnosis, were treated on protocol, or were tested but did not have any record of date of specimen collected, received, or results returned. Multivariable logistic regression was conducted to assess factors associated with PD-L1 testing decisions before 1L therapy start and the association between testing results and choice of 1L treatment. Results: A total of 1,762 patients with R/M HNSCC were included, with 32.0% tested for PD-L1 prior to 1L therapy start, 25.6% tested after, and 42.4% never tested. Most patients were tested using the IHC 22C3 pharmDx assay, an FDA-approved companion diagnostic. Among patients tested before 1L treatment initiation, the most prescribed regimens were pembrolizumab or pembrolizumab + platinum + 5-FU for patients with PD-L1(+) (55.9%, 14.2%) and PD-L1(-) tumors (25.3%, 32.0%), respectively. Patients tested after 1L treatment initiation regardless of CPS and patients never tested were most often prescribed platinum monotherapy for 1L. In a multivariable model, patients who were older, treated in academic settings, HPV(+), or had an ECOG≥2 were more likely to get PD-L1 testing before 1L treatment initiation. Compared to CPS&lt;1, CPS≥20 and 1≤CPS&lt;20 were associated with a higher likelihood of receiving immunotherapy (OR=3.36, 95% CI, 1.69-6.75, p&lt;0.001; OR=3.11, 95% CI, 1.59-6.14, p&lt;0.001, respectively). Conclusions: As an important part of treatment decision-making, PD-L1 testing by CPS should guide 1L single-agent immunotherapy use, but there are many patients not tested before initiating 1L therapy. Age and fitness, clinical practice setting, and HPV status appear to impact testing patterns.[Table: see text]
A genome-wide association study for doxorubicin-induced cardiomyopathy in childhood cancer survivors from the St. Jude lifetime cohort (SJLIFE) and the childhood cancer survivor (CCSS) studies.
Authors: Kateryna Petrykey, Huiqi Wang, Cindy Im, Stephanie B Dixon, Matthew J. Ehrhardt, Daniel A. Mulrooney, Noha Sharafeldin, Xuexia Wang, John L. Jefferies, Kevin C. Oeffinger, Eric Jessen Chow, Maria Monica Gramatges, Smita Bhatia, Leslie L. Robison, Kirsten K. Ness, Melissa M. Hudson, Paul Burridge, Gregory T. Armstrong, Yutaka Yasui, Yadav Sapkota
Journal: Journal of Clinical Oncology (2023)

12088 Background: Treatment of childhood cancer using doxorubicin is associated with a well-established dose-related risk of cardiomyopathy, which can lead to heart failure and affects ~7-10% of exposed children and adolescents. Here, we identified a genetic variant associated with risk of doxorubicin-induced cardiomyopathy (diCM) in survivors of childhood cancer. Methods: A genome-wide association study using common variants (MAF≥5%; whole-genome sequencing data) was performed among 993 SJLIFE survivors of European ancestry (median age, 36.6 years; range, 8.7-62.2 years) treated with doxorubicin only (210 with diCM; defined as CTCAE grade ≥2 clinically assessed cardiomyopathy). Replication analyses were performed separately among 1,430 CCSS survivors of European ancestry (median age, 35.4 years; range, 15.8-60.7 years) and 159 SJLIFE survivors of African ancestry (median age, 32.6 years; range, 8.9-61.1 years) exposed to doxorubicin only. Analyses were adjusted for age at primary cancer diagnosis, sex, doxorubicin dose, age at last contact and top five principal components. Results: We identified a genome-wide significant association between a novel locus near HS3ST4 and diCM risk in SJLIFE survivors of European ancestry (rs112474856; OR = 2.78; P= 3.3×10 -8 ). This association replicated in CCSS survivors of European ancestry (OR = 1.74, P= 0.036) but had an opposite effect among SJLIFE survivors of African ancestry (OR = 0.34, P= 0.028). SNP rs112474856 did not show significant association with diCM risk in two independent datasets including survivors of European ancestry in SJLIFE (OR = 1.20; P= 0.71) and CCSS (OR = 1.02; P= 0.98) who were not exposed to doxorubicin but were treated with daunorubicin or chest radiotherapy, suggesting doxorubicin specificity. No association was observed between rs112474856 and risks of cardiomyopathy (OR = 1.00; P= 0.88) or heart failure (OR = 1.00; P= 0.59) in 361,194 UK Biobank participants from the general population. HS3ST4 was significantly upregulated ( P= 4.7×10 -6 ) in response to doxorubicin treatment in human induced pluripotent stem-cell-derived cardiomyocytes from patients with diCM. HS3ST4 encodes heparan sulfate, the latter was recently linked to immune activation, cardiac fibrosis, and heart failure. Conclusions: Leveraging the two largest cohorts of childhood cancer survivors in North America, we identified and replicated a novel locus for diCM which was associated with increased risk in survivors of European ancestry but decreased in their African counterpart.
Transitions of care with a community-based palliative care program: Results from a pilot project for advanced solid tumor oncology patients.
Authors: Christine Ann Garcia, Ronald D. Adelman, Milagros D. Silva, Sarah Waxse, Linda Morellino, Christopher Comfort, Kelly Cummings
Journal: Journal of Clinical Oncology (2023)

e24113 Background: Hospice underutilization among patients with advanced cancer at the end of life can result in patients not receiving the full benefit of hospice and lead to significant distress to patients, families, staff and caregivers. Through multidisciplinary root cause analyses, we identified a gap in services where hospice care, if pursued at all, did not occur until late in the course. A pilot program for community-based palliative services partnering with Calvary Hospital Advanced Healthcare Coordination was introduced for patients with advanced solid tumor cancer in February 2022. Methods: Solid tumor oncologists, social workers and palliative care physicians identified eligible patients with advanced stage cancer who may or may not be undergoing cancer-directed treatment with palliative intent. Patients received home-based support by palliative trained nurse practitioners, licensed social workers and spiritual counsel including symptom management, advanced care planning, care coordination and hospice transition if indicated. The pilot was launched initially in thoracic oncology in February 2022, with expansion to all solid tumor oncology patients in April 2022. Results: From February 1, 2022 to December 31, 2022, a total of 34 patients were referred for community-based palliative care services. Only 15/34 (44%) referrals were taken under care. Of the patients taken under care 7/15 (46.7%) were eventually transitioned to hospice services, and 4/15 (26.7%) patients expired while receiving community-based palliative care services. Of the remaining patients that were not taken under care (n = 19), 6/19 (31.5%) required a higher level of care and were hospitalized, 4/19 (21.1%) went directly to hospice care. Process measures including pain scores, completion of advanced care planning documents, depression scores, treatments given while in pilot, number of hospitalizations, as well as patient-reported outcomes are ongoing. Conclusions: Our pilot demonstrates that while community-based palliative care services can potentially bridge patients from palliative care services to hospice at the end of life, several patients may still have been referred “too late” in their course. Future plan-do-study-act cycles aim to continue to improve the number and timing of referrals to this pilot program and evaluate its impact in hospice utilization for patients with advanced cancer at end of life.
Methylation-based prediction of myelodysplastic syndrome survival outcomes.
Authors: Alvin Shi, Abdullah Ali, Gordon Cann, Rita Shaknovich, Oliver Venn, Azra Raza, Qinwen Liu
Journal: Journal of Clinical Oncology (2023)

7058 Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid malignancies associated with a myriad of deleterious outcomes and a 5-year relative survival of 37%. MDS risk stratification is key for optimal treatment decisions. DNA methylation is associated with MDS biology due to frequent somatic mutations in genes (i.e. TET2, DNMT3A, IDH1, IDH2, and WT1) that affect DNA methylation. We hypothesized that methylation-based markers may help stratify risk and improve IPSS-R (the Revised International Prognostic Scoring System). Here, we evaluated the potential of both Bone Marrow (BM) Whole-genome Bisulfite Sequencing (WGBS) and Serum-based Targeted Methylation (TM) Sequencing to predict survival of MDS patients. Methods: We conducted paired BM WGBS and Serum-based TM sequencing on a cohort of 127 patients with MDS (N = 104) and secondary AML (N = 23) treated at the Columbia University Medical Center. We categorized patients based on an overall survival of &gt; 3 (“long”, N = 50) or &lt; 3 years (“short”, N = 77). We then identified differentially methylated regions (DMRs) differing between long and short survivor groups, and analyzed the biological pathways and functions enriched in these regions. To assess survival association, we trained a random forest classifier on principal components (“methylation classifier”) on the methylation fractions from a subset of 96 Serum and 98 BM MDS patient samples to predict long vs. short survival, and compared this against a logistic regression IPSS-R model. We optimized the hyperparameters and assessed classifier performance using six-fold nested cross-validation. Finally, we conducted a multivariable cox regression with predicted scores from the methylation classifier, IPSS-R scores (recalculated at sample collection), age, and gender. Results: We identified a total of 7,742 DMRs in the BM WGBS and 14,093 DMRs in the Serum TM as significantly different between long and short survivor groups. Signaling pathways for calcium, cAMP, MAPK, Rap1, and PI3K-Akt were significantly enriched in DMRs. We also identified a previously-reported CpG island hypermethylation signature associated with AML progression in BM and Serum. The methylation classifier achieved a comparable AUROC compared to IPSS-R logistic regression for both BM WGBS (0.80 vs 0.78) and Serum TM (0.77 vs 0.73) samples. Multivariable Cox regression demonstrated that both predicted scores from the methylation classifier (Serum p =0.002; BM p =0.016) and IPSS-R scores (Serum p =0.003; BM p =0.004) are significant predictors of survival. Conclusions: We demonstrated methylation-based sequencing represents a promising new tool for MDS patient risk stratification. As IPSS-R relies on bone marrow aspirates, the Serum-based TM assay offers a less-invasive method for MDS risk stratification.